# Inborn Errors of Immunity Leading to Autoinflammatory Syndromes

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2022 · $502,255

## Abstract

Project Summary
 Albeit rare, monogenic causes of complex disorders provide unique opportunities for a deeper
understanding of common diseases. In this application, we seek to study the molecular pathogenesis of novel,
rare, monogenic autoinflammatory disorders. Central clinical presentations of these syndromic patients include
severe skin inflammation, non-specific gastrointestinal inflammation, and aberrant neurologic features.
 Using whole exome sequencing (WES) we have identified fourteen novel, exceedingly rare, inborn
genetic variations in genes with primary functions in innate immunity, specifically cytokine production,
transduction or regulation. These inborn errors of immunity are putative molecular drivers of autoinflammation,
the mechanisms of which we propose to explore in detail.
 Type I Interferons (IFNs) are cytokines that signal through the JAK-STAT pathway. Beneficial effects of
IFNs largely concern antiviral defense, but profound detrimental effects to human health can manifest if this
pathway is overactive. Mendelian type I Interferonopathy disorders best exemplify how constitutive
upregulation of IFN-I activity can lead to aberrant immune and neurologic features.
 We have recently identified and reported children presenting type I Interferonopathy features due to
complete loss-of-function mutations in either ISG15 or USP18, which are essential for shutting off the IFN-I
response at the IFN-I receptor. These deficiencies are the first genetic defects affecting the negative regulation
of the IFN-I response. In this proposal we seek to characterize patients with novel, complete or hypomorphic,
mutations in these two genes, but also patients who present with alike syndromes with mutations in genes that
either induce IFN-I or convey the signal downstream of IFN-I and other JAK-STAT engaging cytokines.
 We propose to study these rare patients in vitro, ex vivo, and in vivo to determine the molecular,
immunological, and clinical significance of these genes in JAK-STAT pathway regulation, and, by extension,
their function in severe autoinflammatory immune regulation.
 A deeper understanding of the molecular pathophysiology governing these disorders will lay the
groundwork for the development of medicines to better manage persistent inflammatory disorders, rare or
common.

## Key facts

- **NIH application ID:** 10443794
- **Project number:** 5R01AI148963-03
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Dusan Bogunovic
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $502,255
- **Award type:** 5
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10443794

## Citation

> US National Institutes of Health, RePORTER application 10443794, Inborn Errors of Immunity Leading to Autoinflammatory Syndromes (5R01AI148963-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10443794. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*